Targeting cancer with small molecule kinase inhibitors (original) (raw)
Cohen, P. Protein kinases — the major drug targets of the twenty-first century? Nature Rev. Drug Discov.1, 309–315 (2002). CAS Google Scholar
Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science247, 824–830 (1990). CASPubMed Google Scholar
Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med.355, 2408–2417 (2006). CASPubMed Google Scholar
Davies, S. P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J.351, 95–105 (2000). CASPubMedPubMed Central Google Scholar
Lombardo, L. J. et al. Discovery of _N_-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J. Med. Chem.47, 6658–6661 (2004). This paper documents the discovery of dasatinib using a medicinal chemistry approach. CASPubMed Google Scholar
Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science305, 399–401 (2004). This study showed that dasatinib inhibits many imatinib-resistant BCR–ABL1 mutants. CASPubMed Google Scholar
O'Brien, S. G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med.348, 994–1004 (2003). CASPubMed Google Scholar
Weinstein, I. B. et al. Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. Clin. Cancer Res.3, 2696–2702 (1997). CASPubMed Google Scholar
Weinstein, I. B. & Joe, A. K. Mechanisms of disease: Oncogene addiction — a rationale for molecular targeting in cancer therapy. Nature Clin. Pract. Oncol.3, 448–457 (2006). CAS Google Scholar
Futreal, P. A. et al. A census of human cancer genes. Nature Rev. Cancer4, 177–183 (2004). This article features an impressive compilation of genes known to be mutated in cancer. CAS Google Scholar
Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science304, 554 (2004). CASPubMed Google Scholar
Bachman, K. E. et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther.3, 772–775 (2004). CASPubMed Google Scholar
Samuels, Y. et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell7, 561–573 (2005). CASPubMed Google Scholar
Garnett, M. J. & Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell6, 313–319 (2004). CASPubMed Google Scholar
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature417, 949–954 (2002). CASPubMed Google Scholar
Morgan, K. J. & Gilliland, D. G. A role for JAK2 mutations in myeloproliferative diseases. Annu. Rev. Med.59, 213–222 (2008). CASPubMed Google Scholar
Mosse, Y. P. et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature455, 930–935 (2008). CASPubMedPubMed Central Google Scholar
Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer5, 689–698 (2005). CAS Google Scholar
Wang, J. Y., Wilcoxen, K. M., Nomoto, K. & Wu, S. Recent advances of MEK inhibitors and their clinical progress. Curr. Top. Med. Chem.7, 1364–1378 (2007). CASPubMed Google Scholar
Faivre, S., Kroemer, G. & Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nature Rev. Drug Discov.5, 671–688 (2006). CAS Google Scholar
Hu, Y. et al. 90-kDa ribosomal S6 kinase is a direct target for the nuclear fibroblast growth factor receptor 1 (FGFR1): role in FGFR1 signaling. J. Biol. Chem.279, 29325–29335 (2004). CASPubMed Google Scholar
Malumbres, M. & Barbacid, M. Cell cycle kinases in cancer. Curr. Opin. Genet. Dev.17, 60–65 (2007). A comprehensive review of the cell cycle kinases currently being developed as targets for novel inhibitors. CASPubMed Google Scholar
Geiger, T. R. & Peeper, D. S. Critical role for TrkB kinase function in anoikis suppression, tumorigenesis, and metastasis. Cancer Res.67, 6221–6229 (2007). CASPubMed Google Scholar
Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature452, 230–233 (2008). CASPubMed Google Scholar
Jia, S. et al. Essential roles of PI(3)K-p110β in cell growth, metabolism and tumorigenesis. Nature454, 776–779 (2008). CASPubMedPubMed Central Google Scholar
Johnson, L. N., Lowe, E. D., Noble, M. E. & Owen, D. J. The Eleventh Datta Lecture. The structural basis for substrate recognition and control by protein kinases. FEBS Lett.430, 1–11 (1998). CASPubMed Google Scholar
Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science298, 1912–1934 (2002). CASPubMed Google Scholar
Traxler, P. & Furet, P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol. Ther.82, 195–206 (1999). CASPubMed Google Scholar
Liu, Y. & Gray, N. S. Rational design of inhibitors that bind to inactive kinase conformations. Nature Chem. Biol.2, 358–364 (2006). CAS Google Scholar
Hennequin, L. F. et al. N.-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2_H_-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J. Med. Chem.49, 6465–6488 (2006). CASPubMed Google Scholar
Manley, P. W., Cowan-Jacob, S. W. & Mestan, J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim. Biophys. Acta1754, 3–13 (2005). CASPubMed Google Scholar
Wan, P. T. et al. Mechanism of activation of the RAF–ERK signaling pathway by oncogenic mutations of B-RAF. Cell116, 855–867 (2004). CASPubMed Google Scholar
Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell125, 733–747 (2006). An impressive illustration of the integration of chemical and biological approaches to discover and characterize isoform-selective PI3K inhibitors. CASPubMedPubMed Central Google Scholar
Ohren, J. F. et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nature Struct. Mol. Biol.11, 1192–1197 (2004). CAS Google Scholar
Adrian, F. J. et al. Allosteric inhibitors of Bcr-abl-dependent cell proliferation. Nature Chem. Biol.2, 95–102 (2006). CAS Google Scholar
Barnett, S. F. et al. Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors. Biochem. J.385, 399–408 (2005). CASPubMedPubMed Central Google Scholar
Lindsley, C. W. et al. Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem. Lett.15, 761–764 (2005). CASPubMed Google Scholar
McIntyre, K. W. et al. A highly selective inhibitor of IκB kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum.48, 2652–2659 (2003). CASPubMed Google Scholar
Grimsby, J. et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science301, 370–373 (2003). CASPubMed Google Scholar
Guertin, K. R. & Grimsby, J. Small molecule glucokinase activators as glucose lowering agents: a new paradigm for diabetes therapy. Curr. Med. Chem.13, 1839–1843 (2006). CASPubMed Google Scholar
Sullivan, J. E. et al. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett.353, 33–36 (1994). CASPubMed Google Scholar
Sanders, M. J. et al. Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J. Biol. Chem.282, 32539–32548 (2007). CASPubMed Google Scholar
Cohen, M. S., Zhang, C., Shokat, K. M. & Taunton, J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science308, 1318–1321 (2005). This study is an instructive example of how a selective irreversible inhibitor of RSK was designed. CASPubMedPubMed Central Google Scholar
Kwak, E. L. et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl Acad. Sci. USA102, 7665–7670 (2005). CASPubMedPubMed Central Google Scholar
Rabindran, S. K. et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res.64, 3958–3965 (2004). CASPubMed Google Scholar
Kobayashi, S. et al. An alternative inhibitor overcomes resistance caused by a mutation of the epidermal growth factor receptor. Cancer Res.65, 7096–7101 (2005). CASPubMed Google Scholar
Fry, D. W. et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science265, 1093–1095 (1994). CASPubMed Google Scholar
Heymach, J. V., Nilsson, M., Blumenschein, G., Papadimitrakopoulou, V. & Herbst, R. Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin. Cancer Res.12, 4441s–4445s (2006). CASPubMed Google Scholar
Felip, E., Santarpia, M. & Rosell, R. Emerging drugs for non-small-cell lung cancer. Expert Opin. Emerg. Drugs12, 449–460 (2007). CASPubMed Google Scholar
Wissner, A. et al. Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2. Bioorg. Med. Chem.15, 3635–3648 (2007). CASPubMed Google Scholar
Pan, Z. et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. ChemMedChem2, 58–61 (2007). CASPubMed Google Scholar
Cohen, M. S., Hadjivassiliou, H. & Taunton, J. A clickable inhibitor reveals context-dependent autoactivation of p90 RSK. Nature Chem. Biol.3, 156–160 (2007). CAS Google Scholar
Schirmer, A., Kennedy, J., Murli, S., Reid, R. & Santi, D. V. Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides. Proc. Natl Acad. Sci. USA103, 4234–4239 (2006). CASPubMedPubMed Central Google Scholar
Li, B., Liu, Y., Uno, T. & Gray, N. Creating chemical diversity to target protein kinases. Comb. Chem. High Throughput Screen7, 453–472 (2004). CASPubMed Google Scholar
Kraker, A. J. et al. Biochemical and cellular effects of c-Src kinase-selective pyrido[2,3-_d_]pyrimidine tyrosine kinase inhibitors. Biochem. Pharmacol.60, 885–898 (2000). CASPubMed Google Scholar
Mohammadi, M. et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J.17, 5896–5904 (1998). CASPubMedPubMed Central Google Scholar
Lenart, P. et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr. Biol.17, 304–315 (2007). CASPubMed Google Scholar
Sapkota, G. P. et al. BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochem. J.401, 29–38 (2007). CASPubMed Google Scholar
Scotlandi, K. et al. Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors. Cancer Res.65, 3868–3876 (2005). CASPubMed Google Scholar
Okram, B. et al. A general strategy for creating “inactive-conformation” abl inhibitors. Chem. Biol.13, 779–786 (2006). CASPubMed Google Scholar
Dubinina, G. G. et al. In silico design of protein kinase inhibitors: successes and failures. Anticancer Agents Med. Chem.7, 171–188 (2007). CASPubMed Google Scholar
Gill, A. New lead generation strategies for protein kinase inhibitors — fragment based screening approaches. Mini Rev. Med. Chem.4, 301–311 (2004). CASPubMed Google Scholar
Wyatt, P. G. et al. Identification of _N_-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1_H_-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J. Med. Chem.51, 4986–4999 (2008). CASPubMed Google Scholar
Venter, J. C. et al. The sequence of the human genome. Science291, 1304–1351 (2001). CASPubMed Google Scholar
Carter, T. A. et al. Inhibition of drug-resistant mutants of, ABL, KIT, and EGF receptor kinases. Proc. Natl Acad. Sci. USA102, 11011–11016 (2005). CASPubMedPubMed Central Google Scholar
Fabian, M. A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotechnol.23, 329–336 (2005). CAS Google Scholar
Harrington, E. A. et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nature Med.10, 262–267 (2004). CASPubMed Google Scholar
Young, M. A. et al. Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res.66, 1007–1014 (2006). CASPubMed Google Scholar
Fedorov, O. et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc. Natl Acad. Sci. USA104, 20523–20528 (2007). CASPubMedPubMed Central Google Scholar
Warmuth, M., Kim, S., Gu, X. J., Xia, G. & Adrian, F. Ba/F3 cells and their use in kinase drug discovery. Curr. Opin. Oncol.19, 55–60 (2007). CASPubMed Google Scholar
Melnick, J. S. et al. An efficient rapid system for profiling the cellular activities of molecular libraries. Proc. Natl Acad. Sci. USA103, 3153–3158 (2006). CASPubMedPubMed Central Google Scholar
Godl, K. et al. An efficient proteomics method to identify the cellular targets of protein kinase inhibitors. Proc. Natl Acad. Sci. USA100, 15434–15439 (2003). CASPubMedPubMed Central Google Scholar
Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotechnol.25, 1035–1044 (2007). CAS Google Scholar
Peters, E. C. & Gray, N. S. Chemical proteomics identifies unanticipated targets of clinical kinase inhibitors. ACS Chem. Biol.2, 661–664 (2007). CASPubMed Google Scholar
le Coutre, P. et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood95, 1758–1766 (2000). CASPubMed Google Scholar
Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science316, 1039–1043 (2007). This article describes upregulation of an alternative pathway as a mechanism of resistance to kinase inhibitors. CASPubMed Google Scholar
Chu, S. et al. Detection of BCR–ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood105, 2093–2098 (2005). CASPubMed Google Scholar
Hughes, T. & Branford, S. Molecular monitoring of BCR–ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev.20, 29–41 (2006). CASPubMed Google Scholar
Roumiantsev, S. et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc. Natl Acad. Sci. USA99, 10700–10705 (2002). CASPubMedPubMed Central Google Scholar
Fletcher, J. A. & Rubin, B. P. KIT mutations in GIST. Curr. Opin. Genet. Dev.17, 3–7 (2007). CASPubMed Google Scholar
Cools, J. et al. Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res.64, 6385–6389 (2004). CASPubMed Google Scholar
Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood99, 319–325 (2002). CASPubMed Google Scholar
Copland, M. et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood107, 4532–4539 (2006). CASPubMed Google Scholar
Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med.2, e73 (2005). PubMedPubMed Central Google Scholar
Blencke, S. et al. Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors. Chem. Biol.11, 691–701 (2004). This article provides an impressive illustration of the general importance of the gatekeeper position. CASPubMed Google Scholar
Gumireddy, K. et al. A non-ATP-competitive inhibitor of BCR–ABL overrides imatinib resistance. Proc. Natl Acad. Sci. USA102, 1992–1997 (2005). CASPubMedPubMed Central Google Scholar
Gumireddy, K. et al. ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent. Cancer Cell7, 275–286 (2005). CASPubMed Google Scholar
Gorre, M. E., Ellwood-Yen, K., Chiosis, G., Rosen, N. & Sawyers, C. L. BCR–ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR–ABL chaperone heat shock protein 90. Blood100, 3041–3044 (2002). CASPubMed Google Scholar
Copland, M. et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergises with tyrosine kinase inhibitors. Blood111, 2843–2853 (2008). CASPubMed Google Scholar
Hamby, J. M. et al. Structure-activity relationships for a novel series of pyrido[2,3-_d_]pyrimidine tyrosine kinase inhibitors. J. Med. Chem.40, 2296–2303 (1997). CASPubMed Google Scholar
Kothe, M. et al. Selectivity-determining residues in Plk1. Chem. Biol. Drug Des.70, 540–546 (2007). CASPubMed Google Scholar
Weisberg, E. et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr–Abl. Cancer Cell7, 129–141 (2005). CASPubMed Google Scholar
Shah, N. P. et al. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood108, 286–291 (2006). CASPubMed Google Scholar
Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotechnol.26, 127–132 (2008). This article features an impressive profiling of inhibitors against a large panel of kinases. CAS Google Scholar
Vajpai, N. et al. Solution conformations and dynamics of ABL kinase-inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib. J. Biol. Chem.283, 18292–18302 (2008). CASPubMed Google Scholar
Zhou, T. et al. Crystal structure of the T315I mutant of AbI kinase. Chem. Biol. Drug Des.70, 171–181 (2007). CASPubMed Google Scholar
Modugno, M. et al. Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358. Cancer Res.67, 7987–7990 (2007). CASPubMed Google Scholar
Carpinelli, P. et al. PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer. Mol. Cancer Ther.6, 3158–3168 (2007). CASPubMed Google Scholar
Nagar, B. et al. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell112, 859–871 (2003). CASPubMed Google Scholar
Nagar, B. et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res.62, 4236–4243 (2002). CASPubMed Google Scholar